A lot more data is expected from trials with CDK4/6 inhibitors, but part of the issue is going to be will we be using them all? Will they be used in sequence? Is there some unique way to use them with specific patients? All that remains to be defined.

— William J. Gradishar, MD

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Most women with hormone receptor–positive breast cancer receive endocrine therapy as part of their treatment, but “the reality is that patients who receive antihormone therapy in the metastatic disease setting ultimately develop disease progression, ” William J. Gradishar, MD, stated at the 18th Annual Lynn Sage Breast Cancer Symposium, Chicago.1 The challenge is to develop new agents to combat resistance to endocrine therapy and to understand how best to use these new agents against heterogeneous and mutating tumors.

Dr. Gradishar is Betsy Bramsen Professor of Breast Oncology and Deputy Director of the Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine, Chicago. He also served as Chair of the Lynn Sage Breast Cancer Symposium.

‘Ultimately, Tumors Become Refractory’

Current treatments for hormone receptor–positive breast cancer, which accounts for 60% to 70% of all breast cancers, aim to decrease estrogen levels or block the estrogen receptor, but some cancers have de novo resistance, and others acquire resistance over time. “Ultimately, tumors become refractory,” Dr. Gradishar said.

Estrogen receptor mutation “becomes much more common under pressure, as the disease evolves and patients receive endocrine therapy,” Dr. Gradishar added. Several studies suggest that the frequency of those mutations in patients with metastatic disease varies from 19% to 30%, he noted.

“We know from a few trials, that if you have been exposed to tamoxifen, the frequency of those mutations is quite low. But if you receive prior aromatase inhibitor therapy, the frequency of those estrogen receptor mutations go up,” explained Dr. ­Gradishar. Among patients “exposed to both tamoxifen and an aromatase inhibitor, it still looks like the aromatase inhibitor creating an estrogen-deprivation environment is more likely to drive toward the development of an estrogen receptor mutation.” Knowing whether a patient has an estrogen receptor mutation “is something we need to think about, because this biologic information may influence the choice of therapy we offer a patient,” Dr. Gradishar indicated.

Practice-Changing Agent

When estrogen receptor agents stop working, novel agents are needed to overcome other mechanisms of resistance in estrogen receptor–positive breast cancer. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors block the ability of the cell to progress through the cell cycle. The CDK 4/6 inhibitor palbociclib (Ibrance), was approved by the U.S. Food and Drug Administration (FDA) in February 2015 and is now used “quite commonly,” Dr. Gradishar noted. It “has really changed practice to a great degree,” he added.

Two other CDK4/6 inhibitors—ribociclib (LEE011) and abemaciclib (LY2835219)—“are very far along in clinical development,” Dr. Gradishar reported, and “we are going to have to see how they work with respect to each other, whether they have some significant advantages, different toxicity profiles, or can be used in sequence or not.”

The PALOMA trials for palbociclib “were remarkable for the symmetry of the results,” Dr. Gradishar observed. In PALOMA-1, the randomized phase II trial, and PALOMA-2, the randomized phase III trial, comparing letrozole plus palbociclib with letrozole alone, “the median progression-free survival is almost the same. There was an improvement in outcome of about 10 months,” Dr. Gradishar noted. “In PALOMA-3, which represented a patient population who had received prior therapy, there was also a significant improvement in outcome favoring the combination of fulvestrant [Faslodex] and palbociclib.”

The trial design used for the palbociclib studies are similar to that being used to develop ribociclib (the ­MONALEESA trials) and abemaciclib (the MONARCH trials). The ­MONALEESA-2 trial was actually stopped early, as results of a preplanned interim analysis showed the trial met its primary endpoint of clinically meaningful improvement in progression-free survival. Those results were recently published in The New England Journal of Medicine.2

“Abemaciclib received a Breakthrough Designation from the FDA for its development. We don’t have a lot of data based on anything other than early phase I trials showing activity in patients who received prior therapy,” Dr. Gradishar said. He did point out a few interesting things about abemaciclib: “It has monotherapy activity and also seems to have some ability to penetrate the central nervous system, which may be important. And it has a toxicity profile that is a little different from that of palbociclib,” with a bit more gastrointestinal symptoms rather than neutropenia predominating. “So these drugs are not all superimposable,” he continued.

Role for Monotherapy

In the MONARCH I trial, abemaciclib was not combined with endocrine therapy but was used as monotherapy. The clinical benefit rate was 42.4%, and overall survival was 17.7 months.3 “We are most interested in looking at the pivotal trials in combination with endocrine therapy, but monotherapy was actually fairly interesting, even from this relatively small experience,” Dr. Gradishar stated.

In an interview with The ASCO Post, Dr. Gradishar noted: “There are patients who do really well with monotherapy. We might think of those as the exceptional responders, but what we don’t understand is what it is that makes them that way. If we could tease out who the patients are who could do just as well with monotherapy, we could avoid the cost and side effects of the added drugs. The question is, can we identify people who really don’t need the added drug? Not yet.”

“A lot more data is expected from trials with CDK4/6 inhibitors,” Dr. Gradishar added, “but part of the issue is going to be will we be using them all? Will they be used in sequence? Is there some unique way to use them with specific patients? All that remains to be defined.”

Update on HDAC Inhibitors

Inhibitors of histone deacetylase (HDAC), an enzyme that regulates the chromatin structure and gene transcription, may also prove useful in combating tumor growth in women with endocrine-resistant breast cancer. “Using HDAC inhibitors keeps the chromatin open, which may be important particularly if it is a tumor-suppressor gene,” Dr. Gradishar explained.

A large phase III trial is examining the combination of the HDAC inhibitor entinostat and exemestane vs exemestane and placebo in patients with breast cancer who have developed resistance to prior treatment with a nonsteroidal aromatase inhibitor. “We are trying to get this trial done. The increased usage of palbociclib is making this trial somewhat challenging,” Dr. Gradishar commented.

Clinical Issues in Need of Answers

Recent trials have provided “some sense of what the impact of using targeted therapy along with endocrine therapy has been,” Dr. Gradishar recapped. “The utilization of palbociclib compared to an aromatase inhibitor alone, or exemestane plus everolimus [Afinitor], has changed the expected outcomes of patients with estrogen receptor–positive disease.”

He listed several clinical issues for which there are currently no answers.

Who are the exceptional responders to endocrine monotherapy? “We all have them in our clinic. We don’t know who they are before we start treating them, but there are patients who do quite well with monotherapy, meaning endocrine therapy as a single agent.” Dr. Gradishar said. “So does every single patient need to have a combination with one of these agents?

Can biomarkers be identified to define optimal therapy? “We have tried, at least preliminarily, to identify biomarkers that might help us determine who those patients are, but to date, they haven’t been particularly ­successful.”

Can CDK4/6 inhibitors be used in sequence? “We have a variety of these agents in development,” Dr. Gradishar noted. “The challenge, of course, is how are we going to use them? Can abemaciclib be used after palbociclib? Does that even make sense?”

Is there an optimal sequence of combination of targeted therapy with endocrine therapy? “There are going to be multiple agents available,” Dr. Gradishar noted, and using them will become “increasingly complex, potentially toxic, and certainly expensive. So the optimal sequence and combination remain to be determined.”

Changes Over Time

“We understand that if left unattended, a tumor over time evolves and mutates. We also now appreciate that with treatment, a tumor mutates, and there is a great deal of heterogeneity in a tumor,” Dr. Gradishar concluded. “So even with successful targeting, we may still have to confront the problem of tumors that have very different behavior.4 Even with molecular profiling, this is going to be one of the challenges, to understand not just a piece of the tumor but more globally what is going on and what that information does for us as we try to create treatments going forward.”

In response to a question from the audience about whether there would come a time when estrogen receptor antagonists would be replaced by targeted therapy, Dr. Gradishar replied: “Receptor antagonists are probably just that—targeted therapy.” He considered “endocrine therapy as the first targeted therapy, and the newer ones are more of the same, but at a different molecular level.” With all that goes on within a tumor and the changes over time, many different targeted therapies will be needed, Dr. Gradishar concluded. “I don’t think we will be using one exclusively if we have hopes of eradicating tumors.” ■